Petar Milovanovic

Cadmium (Cd) is a ubiquitous environmental pollutant that enters the circulation from the lungs and gastrointestinal tract. For most people, staple foods form the main route of Cd exposure. Current evidence suggests that Cd may increase the prevalence of iron deficiency and anemia in environmentally exposed people. Concerningly, intravenous iron administration to treat iron deficiency anemia has resulted in adverse bone outcomes at a higher-than-expected frequency, for which reasons remain unclear. The bone-derived hormone fibroblast growth factor 23 (FGF23), the regulator of vitamin D and phosphate homeostasis, has been speculated to be implicated, given that anemia, iron deficiency and inflammatory conditions are all known to increase FGF23 expression levels in osteoblasts. Additionally, early studies have demonstrated that Cd increases FGF23 expression by osteoblast-like cells and suppresses FGF23 cleavage, leading to an abrupt rise in serum FGF23, which, in turn, mediates an effect of Cd on tubular phosphate reabsorption. In this review, experimental breakthrough studies showing Cd-induced iron deficiency and a reduction in iron absorption by Cd are summarized, together with intestinal absorption of Cd and an increment in Cd uptake and Cd body burden in those with low body iron stores. Potential contributions of Cd, anemia and iron deficiency in the context of hypophosphatemic osteomalacia development after intravenous iron supplementation are discussed. The molecular basis of Cd-induced ferroptosis in pathogenesis of osteoporosis, emphasizing heme oxygenase-1 (HO-1)/bilirubin axis and zinc deficiency, is presented.

Cadmium (Cd) is a ubiquitous environmental pollutant that enters the circulation from the lungs and gastrointestinal tract. For most people, staple foods form the main route of Cd exposure. Current evidence suggests that Cd may increase the prevalence of iron deficiency and anemia in environmentally exposed people. Concerningly, intravenous iron administration to treat iron deficiency anemia has resulted in adverse bone outcomes in a higher-than-expected frequency; for which reasons remain unclear. The bone-derived hormone, fibroblast growth factor 23 (FGF23), the regulator of vitamin D and phosphate homeostasis, has been speculatively implicated, given that anemia, iron deficiency and inflammatory conditions all are known to increase FGF23 expression levels in osteoblasts. Additionally, early studies demonstrated that Cd increased FGF23 expression by osteoblast-like cells and suppressed FGF23 cleavage leading to an abrupt rise in serum FGF23, which, in turn, mediated an effect of Cd on tubular phosphate reabsorption. In this review, experimental breakthrough studies showing Cd-induced iron deficiency, and a reduction in iron absorption by Cd are summarized together with intestinal absorption of Cd, and an increment of Cd uptake and Cd body burden in those with low body iron stores. Potential contributions of Cd, anemia and iron deficiency in the context of hypophosphatemic osteomalacia development after intravenous iron supplementation, are discussed. Mechanism of Cd-induced ferroptosis in pathogenesis of osteoporosis, emphasizing heme oxygenase-1 (HO-1)/bilirubin axis and zinc deficiency are presented.

Background: Endocrine science remains underrepresented in European Union research programmes despite the fundamental role of hormone health in human well-being. Analysis of the CORDIS database reveals a persistent gap between the societal impact of endocrine disorders and their research prioritization. At national funding level, endocrine societies report limited or little attention of national research funding towards endocrinology. The EndoCompass project—a joint initiative between the European Society of Endocrinology and the European Society of Paediatric Endocrinology—aimed to identify and promote strategic research priorities in endocrine science to address critical hormone-related health challenges. Methods: Research priorities were established through comprehensive analysis of the EU CORDIS database covering the Horizon 2020 framework period (2014-2020). Expert consultation in bone and calcium endocrinology was conducted to identify key research priorities, followed by broader stakeholder engagement including society members and patient advocacy groups. Results: Research priorities encompass primary hyperparathyroidism, chronic hypoparathyroidism, and rare calcium–phosphate disorders. Key areas include bone as endocrine organ, bone mass acquisition, secondary osteoporosis, and skeletal dysplasias. Special emphasis is placed on cellular senescence, sex-specific differences in disease manifestation, and development of novel diagnostic tools for bone quality assessment. Conclusions: This component of the EndoCompass project provides an evidence-based roadmap for strategic research investment. This framework identifies crucial investigation areas into metabolic bone disease pathophysiology, prevention, and treatment strategies, ultimately aimed at reducing the burden of these disorders on individuals and society. The findings support the broader EndoCompass objective of aligning research funding with areas of highest potential impact in endocrine health.

Objective: The cave site of Velika Balanica in Sićevo Gorge, Serbia, has previously yielded early Neanderthal dental remains from Layer 3a, dated by thermoluminescence to 285 ± 34 and 295 ± 74 ka. We describe and compare four additional dental specimens recovered from the Middle Pleistocene Layers 3a and 3b of the cave: a right I ¹ (BH‐8), a right I ₂ (BH‐7), an incisor crown fragment (BH‐16), and a left M ₃ (BH‐15). Material and Methods: The fossil teeth were scanned using micro‐computed tomography (μCT), and the resulting digital models were used to record dimensions and assess internal morphology, including the enamel–dentine junction (EDJ). Morphological traits were analyzed on both outer and internal surfaces. Dental measurements were compared to those of relevant hominin samples. Results: BH‐8 and BH‐7 show large, robust crowns and roots, consistent with Pleistocene Eurasian hominins. Linear enamel hypoplasia is present in BH‐8 and BH‐16. BH‐15 displays a continuous middle trigonid crest—a trait considered diagnostic of the Neanderthal lineage. Notably, BH‐15 also presents an extreme case of taurodontism, as well as a severe antemortem tooth fracture accompanied by multiple pulp stones, which are rarely recorded in the hominin fossil record. Discussion: These findings align with earlier results, reinforcing evidence for early Neanderthal presence at Velika Balanica around 300 ka. While Neanderthals may have been present in the region earlier, this represents the earliest dated evidence of their spread into the Balkans.

This study aimed to perform microstructural characterization of the increased fragility of human bone in type 2 diabetes mellitus (T2DM) by exploring the matrix mineralization and osteocyte lacunar density at the superolateral femoral neck—the typical fracture-initiating site. Postmortem specimens of the full-length superolateral femoral neck from 16 elderly men with T2DM and age-matched non-DM controls were examined using backscattered-electron microscopy in terms of mineralization parameters and parameters of osteocyte lacunar density. The T2DM and control groups did not differ in age and body mass index (p > 0.05). In the endocortical region, T2DM was associated with a lower degree of mineralization (lower CaMean: p = 0.04), a higher proportion of extremely low-mineralized areas (higher CaLow: p = 0.027), and greater mineralization heterogeneity (higher CaWidth: p = 0.003) relative to controls. However, there were no significant intergroup differences in mineralization parameters in the periosteal region. In the endocortical region, T2DM showed lower unmineralized (p = 0.006) and total osteocyte lacunar number (Lc.N) per bone area (B.Ar) (p = 0.018) coupled with a higher percentage of mineralized lacunae (%Mn.Lc) relative to controls (p = 0.05). In the periosteal region, only Lc.N/B.Ar was lower in T2DM (p = 0.004). As for the trabecular compartment, T2DM was associated with lower trabecular CaMean (p = 0.048) and higher trabecular CaLow and CaWidth (p = 0.005, p = 0.007). Altered pattern of mineralization in the cortical (especially in the endocortical region) and trabecular compartments of the superolateral femoral neck and reduced cortical osteocyte lacunar density are structural hallmarks of bone fragility in T2DM.

Low bone quality has been reported as a source of bone fragility in individuals with alcohol-associated liver disease (AALD). Alterations of the bone matrix, including the spatial BMD distribution and osteocyte lacunar network characteristics, have not been comprehensively assessed in common fracture sites of individuals with AALD. Considering the clinical relevance of vertebral and femoral fragility fractures among these individuals, this cross-sectional study aimed to analyze site-specific BMD distribution, bone mechanical properties, osteocyte lacunar network, and Haversian system characteristics in the first lumbar vertebra and superolateral femoral neck of adult male donors with AALD. Quantitative backscattered electron imaging and Vickers micro-indentation testing were conducted to analyze bone quality in specimens from vertebral and femoral bone harvested at autopsy from adult male donors (n = 24), divided into 2 groups: AALD group (12 individuals with histopathological confirmation of AALD, age: 60 ± 12 yr) and age-matched controls (12 individuals without histopathological features of liver disease, age: 59 ± 12 yr). The comparative assessment revealed significantly lower mean calcium content, reduced Vickers micro-hardness, higher density of osteocyte lacunae occluded with mineralized matter (ie, micropetrosis), thicker osteonal wall, and a higher percentage of osteon refilling in lumbar vertebrae and superolateral femoral neck obtained from the AALD group (p < .05). Although bone quality alterations were congruent in both skeletal sites, the most severe AALD-induced impairment was noted in the trabecular compartment of lumbar vertebrae (p < .05). Our findings revealed a site-specific reduction in trabecular bone mineralization and an increased proportion of mineralized osteocyte lacunae in male individuals with AALD, which may contribute to increased vertebral predilection in these individuals.

Increased urine and blood concentrations of heavy metals are linked to an elevated hip fracture risk, but studies dedicated to directly measuring metal(oid) concentrations in the femoral neck are limited. We investigated whether individuals with fractures exhibit a different pattern of metal(oid) bioaccumulation in the femoral neck and examined potential correlations between the concentrations of various metal(oid)s in the femoral neck and trabecular microarchitecture. To address these objectives, we collected femoral neck specimens from 23 individuals, namely 11 individuals with a positive history of contralateral hip fracture (9 women and 2 men, mean age 77.7 ± 8.1 years) and 12 individuals without fractures (10 women and 2 men, mean age 79.5 ± 5.6 years). All samples were subject to microcomputed tomography (micro-CT) to evaluate bone microarchitecture and inductively coupled plasma–mass spectrometry to determine tissue concentrations of metal(oid)s. In the fully adjusted model (adjusted for bone volume, age, and calcium tissue concentration), individuals with hip fractures exhibited higher aluminum levels (p = 0.047) and lower vanadium levels (p < 0.001). Individuals who sustained fragility fractures also showed lower BV/TV, Tb.Th, Tb.N, and higher Tb.Sp in the femoral neck trabeculae compared with the control group. Several different metal(oid)s were associated with altered patterns of trabecular microarchitecture. In summary, higher aluminum and lower vanadium concentrations in the trabeculae of the femoral neck provide a potential background for the gradual increase in fracture risk. Correlational analysis revealed an association between exposure to certain metals and deteriorated trabecular microarchitecture; however, larger studies are needed to determine the elements independently affecting bone microarchitecture. Graphical abstract

Background: Doctoral programmes are an important pillar of medical education, and although many universities award the best theses, the criteria for selection of awardees and the topics of their doctoral theses are seldom analysed. Objectives: To analyse the landscape of doctoral research through assessing the temporal trends in the criteria related to recognising the best theses. Methods: A total of 55 award-winning doctoral theses, from those submitted to the Faculty of Medicine, University of Belgrade, over 7 years (2016–2022), were examined, focusing on the number of awardees, publications based on the theses, research subfields, and keywords. Results: The awardees comprised 36 women (65%) and 19 men (35%). The number of award-winning theses per year in clinical medicine and public health increased over the years (P < .05 for both the fields). The awardees had published a total of 134 articles based on their theses before the thesis defence, and half of these were published in open-access journals. The journals that each published at least 4 of these articles were PLOS One, Experimental and Molecular Pathology, and Oxidative Medicine and Cellular Longevity. The cumulative impact factor of these publications showed no significant increase (P > .05). The subfields that accounted for at least 5 of the publi-cations were molecular medicine (13 publications) among the basic or translational fields, cardiology (5) among clinical medicine, and epidemiology (7) among public health. Mapping the co-occurrence of keywords from all the dissertations identified some research hotspots, which included cancer, oxidative stress, Parkinsonism, risk factors, genetic polymorphisms, and biomarkers. Conclusion: The increasing number of award-winning theses reflects the rising quality of doctoral research and the growing motivation of candidates to choose indexed journals as outlets for papers based on the theses. This approach can serve as a basis for strategic evaluation of the practices for evaluating PhD theses and for identifying strong and weak spots in the research landscape of medical schools to guide future doctoral research and the competitiveness of doctoral programmes.